Amide compounds, process for preparing the same, and composition for activating gastric motor function containing the same

ABSTRACT

Amide-compounds represented by the formula (I): ##STR1## wherein R 1  represents hydrogen, lower alkoxy, hydroxy, lower alkyl, halogen, amino which can be substituted by lower alkyl, nitro, cyano, sulfamoyl which can be substituted by lower alkyl, R 2  represents hydrogen, lower alkoxy, hydroxy, lower alkyl, halogen, amino, nitro, wherein R 1  and R 2  can be combined to form methylenedioxy, R 3  means hydrogen, lower alkyl, halogen, or amino, R 4  and R 5  may be the same or different and each represents lower alkyl or wherein R 4  and R 5  may be combined together with nitrogen to form 1-pyrrolidinyl or piperidino, and pharmacologically-acceptable acid-addition salts thereof, which exhibit excellent effects in the activation of gastric motor function, a process for preparation pharmaceutical compositons thereof, as well as a method for the treatment of a subject suffering from an ailment associated with inadequate gastric motor function by administrating such a compound to the said subject, are all disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel amide compounds represented bythe following general formula (I) as well as acid addition saltsthereof, process for preparing the same, and a composition foractivating gastric motor function containing the same as activeingredient which can be used in the treatment of related ailments.##STR2##

2. Description of the Prior Art

It is already known thatN-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide [generalname, TRIMETHOBENZAMIDE, The United States Pharmacopeia XXI, 1094(1985)] represented by formula (II), ##STR3## can be used only as anantiemetic drugs and is not used for activating gastric motor function.

Non-ulcer dyspepsia such as gastric discomfort and abdominal distensionresults in part from a decrease of gastric motor function. Therefore, itis necessary to administer a drug which has the action on activatinggastric motor function, so that such symptons can also be alleviated.

So far, as a medicament which has the action on activating gastric motorfunction, 4-Amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide(general name, Metoclopramide, The Merck Index 10th Edition, 6019)represented by formula (III) is known. ##STR4##

But this medicament has also the antiemetic effect. Medicaments such asthis one are not satisfactory for practical use because of insufficientefficacy and having the serious side effects.

Accordingly, there has been a need for a new and useful medicament forthe activation of the gastric motor function.

3. Summary of the Invention

It has been found surprisingly, that the amide compounds represented bythe formula (I): ##STR5## wherein R₁ represents hydrogen, lower alkoxy,hydroxy, lower alkyl, halogen, amino which can be substituted by loweralkyl, nitro, cyano, sulfamoyl which can be substituted by lower alkyl,R₂ represents hydrogen, lower alkoxy, hydroxy, lower alkyl, halogen,amino, nitro, wherein R₁ and R₂ can be combined to form methylenedioxy,R₃ means hydrogen, lower alkyl, halogen, or amino, R₄ and R₅ may be thesame or different and each represents lower alkyl or wherein R₄ and R₅may be combined together with nitrogen to form 1-pyrrolidinyl orpiperidino, and pharmacologically-acceptable acid-addition saltsthereof, exhibit excellent effects in the activation of gastric motorfunction.

Further, according to the present invention, there are provided also aprocess for preparation of the novel amide compounds represented by thegeneral formula (I), pharmaceutical compositions useful to activategastric motor function comprising one or more compounds as representedby the formula (I) in an amount effective for such purpose, as well as amethod for the treatment of a subject suffering from an ailmentassociated with inadequate gastric motor function by administrating sucha compound to the said subject.

DETAILED DESCRIPTION OF THE INVENTION

By the term "lower" in formula (I) is meant a straight or branchedcarbon chain having 1-4 carbon atoms, inductively. Therefore the loweralkyl moiety of the lower alkyl group encompassed by R₁, R₂, R₃, R₄ andR₅ is representatively methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, etc. The lower alkoxy moiety of thelower alkoxy group is representatively methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, etc. As halogen represented by R₁, R₂ and R₃ canbe used: fluorine, chlorine and bromine, etc. Examples of amine, whichmay be substituted by lower alkyl are amino, methylamino, dimethylamino,and diethylamino, etc. and examples of sulfamoyl group, which may besubstituted by lower alkyl are sulfamoyl, methylaminosulfonyl anddimethylaminosulfonyl, etc.

The compounds represented by the formula (I) can be converted to theirpharmacologically-acceptable acid-addition salts in the usual manner andthe free base can be liberated from the resulting salts if desired.

Pharmacologically-acceptable acid-addition salts of the amide compoundsrepresented by the formula (I) include, for example, mineral salts suchas hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and thelike, or organic acid salts such as acetate, maleate, fumarate, citrate,oxalate, lactate, malate, tartarate, and the like.

The novel amide-compounds represented by the general formula (I) can beprepared as follows:

A functional derivative such as the chloride or other halide, theanhydride or a mixed anhydride, of a carboxylic acid represented by theformula (IV) ##STR6## wherein R₁, R₂ and R₃ each has the same meaning asdescribed above, is reacted with an amino-compound represented by theformula (V) ##STR7## wherein R₄ and R₅ each has the same meaning asdescribed above, in the presence or absence of a base and in thepresence of an inert organic solvent.

Bases which can be used in this method are, for example, pyridine,picoline, lutidine, collidine, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, triethylamine, potassium carbonate, sodiumcarbonate, or the like.

The solvent used in this reaction can be any kind of solvent which doesnot inhibit the reaction. Examples of the inert organic solvent whichmay be used are ether, benzene, toluene, ethyl acetate, tetrahydrofuran,dioxane, chloroform, methylenechloride, dimethylsulfoxide, andN,N-dimethylformamide.

The reaction is generally carried out at a temperature within the rangeof 0° C. to the reflux temperature of the reaction solvent employed.

The starting materials represented by the above formula (V), most ofwhich are novel compounds, can be prepared by a process shown in thefollowing scheme: ##STR8## wherein R₄ and R₅ each has the same meaningas described above and X represents a halogen.

The most important compounds of this invention are for example asfollows:

N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide,N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamidehydrochloride, 3,4-Methylenedioxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl] benzamide, 3,4-Dimethoxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide,N-[4-[2-(dimethylamino)ethoxy]benzyl]-4-ethoxy-3-methoxybenzamide,N-[4-[2-(dimethylamino)ethoxy]benzyl]-2-methoxy-5-sulfamoylbenzamide,and 4-amino-5-chloro-2-methoxy-N-[4-[2-(1-pyrrolidinyl) ethoxy]benzyl]benzamide.

A compound of the present invention represented by general formula (I)can be administrated per os, e.g., in the form of pills or tablets, inwhich it may be present together with any of the usual pharmaceuticalcarriers, conventionally by compounding a compound of this inventiontogether with a customary carrier or adjuvant, such as talc, magnesiumstearate, starch, lactose, gelatin, any of numerous gums, or the like.Thus, in their most advantageous form, the compositions of thisinvention will contain a non-toxic pharmaceutical carrier in addition tothe active ingredient of the present invention. Exemplary solid carriersare lactose, magnesium stearate, calcium stearate, starch, D-mannitol,crystalline cellulose, or the like. Representative liquid carriers arewater, sesame oil, olive oil, propylane glycol, or the like. The activeagents of this invention can be conveniently administered in suchcompositions containing active ingredient so as to be within the dosagerange illustrated hereinafter. Thus, a wide variety of pharmaceuticalforms suitable for many modes of administration and dosages may beemployed. For oral administration, the active ingredient andpharmaceutical carrier may, for example, take the form of a powder,granule, pill, tablet, capsule, lozenge, elixir, syrup, or other liquidsuspension or emulsion whereas, for parenteral administration, thecomposition may be in the form of a sterile solution. For intra-rectaladministration, the composition may be in the form of a suppository.

The method of using the compounds of this invention comprises internallyor externally administering a compound of this invention, preferablyorally or parenterally and preferably admixed with the pharmaceuticalcarrier, for example, in the form of any of the above compositions, orfilled into a capsule, to alleviate conditions to be treated andsymptoms thereof in a living animal body. Illustratively, it may be usedin an amount of about 1.0 to about 1000 mg per day for oraladministration, and about 1.0 to about 500 mg per day for a parenteraladministration. The unit dose is preferably given a suitable number oftimes daily, typically three times.

The unit dose may vary depending upon the number of times given in anytime period. Naturally, a suitable clinical dose must be adjusted inaccordance with the condition, age, and weight of the patient, and itgoes without saying that the enhanced activities of the compounds of theinvention, together with their reduced side effects, also make themsuitable for wide variations, and this invention therefore should not belimited by the exact ranges stated. The exact dosage, both unit dosageand daily dosage, will of course have to be determined according toestablished medical principles.

The following experiments show with the excellent effect of the presentcompounds (Compound No. means Example Compound No.), while usingmetoclopramide hydrochloride (III HCl) and trimethobenzamidehydrochloride (II HCl) as reference compounds.

Experiment 1

Contractile effects of the test compounds in isolated guinea pig ileum

Male Hartley guinea-pigs weighing about 450 g were sacrificed and theileum was excised. Then intact strips 1.5-2.0 cm long were prepared.These preparations were suspended vertically in an organ bath filledwith Krebs-Henseleit's solution at 37° C. which was gassed with 95% O₂and 5% CO₂. Rhythmic contractions of the preparations were isotonicallymeasured. Effects of the test compounds were assessed as the relativepercentage of a test compound against 10⁻⁶ M acetylcholine-inducedcontractions. Results were as follows (Table 1).

                  TABLE 1                                                         ______________________________________                                        Test compounds         ED.sub.50 (M)*                                         ______________________________________                                        Compound 2             6.0 × 10.sup.-7                                  Compound 3             4.6 × 10.sup.-7                                  Compound 5             1.8 × 10.sup.-7                                  Compound 6             4.0 × 10.sup.-7                                  Compound 7             3.0 × 10.sup.-7                                  Compound 8             1.6 × 10.sup.-6                                  Compound 14            6.9 × 10.sup.-7                                  Compound 19            4.2 × 10.sup.-7                                  Compound 20            5.0 × 10.sup.-7                                  Compound 23            3.0 × 10.sup.-7                                  Compound 24            6.1 × 10.sup.-7                                  Compound 25            6.8 × 10.sup.-7                                  Compound 31            4.2 × 10.sup.-7                                  Compound 32            1.4 × 10.sup.-7                                  Compound 34            1.2 × 10.sup.-7                                  Compound 35            4.9 × 10.sup.-7                                  Compound 36            3.4 × 10.sup.-7                                  Compound 37            1.8 × 10.sup.-7                                  Compound 38            3.5 × 10.sup.-7                                  Compound 39            3.9 × 10.sup.-7                                  Compound 40            6.0 × 10.sup.-7                                  Compound 41            1.3 × 10.sup.-7                                  Compound 42            < 10.sup.-7                                            Compound 43            < 10.sup.-7                                            Compound 45            4.6 × 10.sup.-6                                  Compound 47            3.0 × 10.sup.-6                                  Compound 48            5.1 × 10.sup.-7                                  Compound 51            6.1 × 10.sup.-7                                  Compound 52            4.5 × 10.sup.-7                                  Compound 53            4.6 × 10.sup.-7                                  Compound 55            1.3 × 10.sup.-6                                  Compound 56            3.2 × 10.sup.-7                                  Compound 57            9.3 × 10.sup.-7                                  Compound 58            4.2 × 10.sup.-7                                  Compound 59            6.2 × 10.sup.-7                                  Compound 62            3.9 × 10.sup.-7                                  Compound 63            5.0 × 10.sup.-7                                  Metoclopramide HCl     6.3 × 10.sup.-6                                  Trimethobenzamide HCl  1.5 × 10.sup.-6                                  ______________________________________                                         *The dose which evoked 50% of the acetylcholineinduced contraction.      

These results showed that compound 2 had about 10 times and about 2.5times stronger contractile effect than metoclopramide.HCl andtrimethobenzamide.HCl respectively.

Experiment 2

Improving effects of the test compound on dopamine-induced suppressionof gastrointestinal transit in mice

Male mice of the ddY strain weighing about 22 g were fasted overnightand the test compounds (suspended in 0.5% carboxymethylcellulose) wereadministered orally. Thirty minutes later dopamine (2 mg/kg dissolved insaline) or saline only was administered intraperitoneally followedimmediately by the oral administration of charcoal meal (5% charcoalpowder suspended in 10% gum arabic). Twenty minutes later the animalswere sacrificed and the digestive tracts were isolated from the stomachto the cecum. The gastrointestinal transit was determined by calculatingthe total intestinal length between the pylorus and the cecum and thelength over which charcoal meal was carried from the pylorus.Statistical analysis was carried out by Student's t-test for unpairedobservations. Results were as follows (Table 2).

                  TABLE 2                                                         ______________________________________                                                     Dose           Gastrointestinal                                                                        Improve-                                Experimental (mg/kg,        transit   ment                                    group        p.o.)    n     (% ± S.E.)                                                                           (%)                                     ______________________________________                                        Control      --       10     53.3 ± 2.0**                                  Dopamine alone                                                                             --       12    31.7 ± 3.2                                     Compound 2 + 30       11     43.9 ± 2.8**                                                                        56.5                                    Dopamine                                                                      Control      --       11     53.3 ± 2.0**                                  Dopamine alone                                                                             --       12    31.7 ± 3.2                                     Compound 3 + 30       10     44.0 ± 4.7*                                                                         56.9                                    Dopamine                                                                      Control      --       10     50.1 ± 3.0**                                  Dopamine alone                                                                             --       10    25.0 ± 3.4                                     Compound 18 +                                                                              30       10     43.0 ± 6.5*                                                                         71.7                                    Dopamine                                                                      Control      --       12     51.8 ± 1.7**                                  Dopamine alone                                                                             --       13    35.9 ± 2.1                                     Compound 31 +                                                                              30       12     45.2 ± 3.0*                                                                         58.5                                    Dopamine                                                                      Control      --       10     54.5 ± 3.4**                                  Dopamine alone                                                                             --       10    32.9 ± 3.1                                     Compound 34 +                                                                              30       11     46.6 ± 3.4*                                                                         63.4                                    Dopamine                                                                      Control      --       22     50.9 ± 2.1**                                  Dopamine alone                                                                             --       22    32.1 ± 2.0                                     Metoclopramide                                                                             30       9     37.2 ± 3.2                                                                           27.1                                    .HC1 + Dopamine                                                               Control      --       22     50.9 ± 2.1**                                  Dopamine alone                                                                             --       22    32.1 ± 2.0                                     Trimethobenzamide                                                                          30       13    38.2 ± 3.8                                                                           32.4                                    .HC1 + Dopamine                                                               ______________________________________                                         * and **: Significantly different from groups treated with dopamine at P      0.05 and P < 0.01, respectively.                                         

It is concluded that the compounds of this invention showed significantimprovement of gastrointestinal transit which was inhibited by dopamineat a dose of 30 mg/kg, but that the antiemetic drugs bothmetoclopramide.HCl and trimethobenzamide.HCl did not so only to a muchlesser extent.

Experiment 3

Suppressing effects of the test compounds on apomorphine-induced emesisin beagle dogs

Male beagle dogs weighing about 8 kg were fasted overnight. The testcompounds (suspended or dissolved in 0.5% CMC) were administered orallyand the dogs fed fortyfive minutes later. Then, fifteen minutes later100 mg/kg apomorphine (dissolved in saline) was administeredsubcutaneously and emetic events were observed for sixty minutes.

As a consequence, and as expected the antiemetic drugs metoclopramideHCl and trimethobenzamide.HCl showed the significant antiemetic effectat doses of 1 mg/kg and 30 mg/kg, respectively. The compound 2 showshowever slight antiemetic effect at a dose of 30 mg/kg.

Experiment 4

Acute toxicological study in mice

Male ICR mice aged 5 weeks were used for each determination. The testcompounds (2-4 different doses) were intravenously administered and LD₅₀values were calculated using the up and down method. Results were asfollows (Table 3).

                  TABLE 3                                                         ______________________________________                                        Test compounds LD.sub.50 (mg/kg)                                              ______________________________________                                        Compound 2     190.6                                                          Compound 3     62.6                                                           Compound 5     94.0                                                           Compound 6     39.2                                                           Compound 8     85.1                                                           Compound 19    70.8                                                           Compound 23    74.1                                                           Compound 25    87.1                                                           Compound 31    104.7                                                          Compound 32    112.2                                                          Compound 34    44.7                                                           Compound 35    61.7                                                           Compound 47    68.5                                                           Compound 48    83.2                                                           Compound 51    85.9                                                           Compound 53    77.6                                                           ______________________________________                                    

The following prescriptive examples and examples are given by wayillustration only and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe scope and apirit thereof.

    ______________________________________                                        Prescriptive Example 1: Capsule Formulation (hard capsule)                    ______________________________________                                        Compound of Example 2                                                                          50 mg                                                        Lactose          a proper quantity                                            Corn Starch      20 mg                                                        Magnesium Stearate                                                                              1 mg                                                                         to 130 mg                                                    ______________________________________                                    

    ______________________________________                                        Prescriptive Example 2: Tablet Formulation                                    ______________________________________                                        Compound of Example 5                                                                             50 mg                                                     Lactose             a proper quantity                                         Corn Starch         20 mg                                                     Magnesium Stearate  2 mg                                                      Hydroxypropylmethyl cellulose                                                                     8 mg                                                      Polyethyleneglycol  1 mg                                                      Titanium Oxide      1 mg                                                                          to 210 mg                                                 ______________________________________                                    

    ______________________________________                                        Prescriptive Example 3: Granule Formulation                                   ______________________________________                                        Compound of Example 2                                                                          100 mg                                                       Lactose          a proper quantity                                            D-Mannitol       500 mg                                                       Hydroxypropyl cellulose                                                                         20 mg                                                       Talc              2 mg                                                                         to 1000 mg                                                   ______________________________________                                    

    ______________________________________                                        Prescriptive Example 4: Injection Formulation                                 ______________________________________                                        Compound of Example 6 (hydrochloride)                                                                50 mg                                                  Citric acid            0.5 mg                                                 Sodium Hydroxide       a proper quantity                                      Distilled Water for Injection                                                                        a proper quantity                                                             to 1 ml                                                ______________________________________                                    

    ______________________________________                                        Prescriptive Example 5: Suppository Formulation                               ______________________________________                                        Compound of Example 48 (hydrochloride)                                                                 50      mg                                           Hard Fat                 1250    mg                                                                    to 1300 mg                                           ______________________________________                                    

Reference 1 4-[2-(Dimethylamino)ethoxy] benzaldehyde

To a solution of 61.1 g of p-hydroxybenzaldehyde in 240 ml ofN,N-dimethylformamide was added 138 g of potassium carbonate, 80.7 g of2-dimethylaminoethyl chloride and 30 ml of isopropyl ether. The mixturewas stirred at 60° C. for 1.5 hours. After cooling, the reaction mixturewas poured into 720 ml of water, and the whole was extracted withchloroform. The chloroform layer was extracted with aqueous hydrochloricacid. The aqueous layer was made alkaline with aqueous sodium hydroxidesolution and extracted with ethyl acetate. The extract was washed withwater, dried and evaporated. The residue was distilled to give 69.1 g ofcolorless oil, b.p. 142°-144° C. (4 mmHg).

NMR spectrum δ (CDCl₃)ppm: 2.34 (6H,s), 2.76 (2H,t,J=6 Hz), 4.15(2H,t,J=6 Hz), 7.02 (2H,d,J=9 Hz), 7.82 (2H,d,J=9 Hz), 9.87 (1H,s).

Reference 2 4-[2-(1-Pyrrolidinyl)ethoxy]benzaldehyde

A mixture of 2.29 g of 4-(2-bromoethoxy)benzaldehyde, 1.42 g ofpyrrolidine and 2.07 g of potassium carbonate in 8 ml ofN,N-dimethylformamide was stirred at 60° C. for 2 hours. After cooling,water was added and the whole was extracted with ethyl acetate. Theethyl acetate layer was extracted with aqueous hydrochloric acid. Theaqueous layer was made alkaline with potassium carbonate and extractedwith ethyl acetate. The extract was washed with water, dried andevaporated. The residue was distilled to give 1.72 g of colorless oil,b.p. 170° C. (5 mmHg).

NMR spectrum δ (CDCl₃)ppm: 1.60-2.27 (4H,m), 2.44-2.80 (4H,m), 2.93(2H,t,J=6 Hz), 4.19 (2H,t,J=6 Hz), 7.01 (2H,d,J=9 Hz), 7.82 (2H,d,J=9Hz), 9.87 (1H,s).

In the same manner as described in Reference 1 and 2, the compound inReference 3 was prepared.

Reference 3 4-(2-Piperidinoethoxy)benzaldehyde

Colorless oil, b.p. 160°-162° C. (6 mmHg).

NMR spectrum δ (CDCl₃)ppm: 1.12-1.76 (6H,m), 2.27-2.61 (4H,m), 2.79(2H,t,J=6 Hz), 4.18 (2H,t,J=6 Hz), 7.00 (2H,d,J=9 Hz), 7.82 (2H,d,J=9Hz), 9.87 (1H,s).

Reference 4 4-[2-(Dimethylamino)ethoxy]benzaldoxime

A mixture of 154 g of 4-[2-(dimethylamino)ethoxy]benzaldehyde and 59.9 gof hydroxyamine hydrochloride in 600 ml of ethanol was boiled for 10minutes. After cooling, the precipitate was filtered to givehydrochloride as pale yellow crystals, m.p. 174°-175° C. These crystalswere dissolved in 150 ml of water. The solution was made alkaline withpotassium carbonate and extracted with chloroform. The extract was driedand evaporated. The residue was washed with isopropyl ether to give 157g of colorless crystals, which were recrystallized from ethyl acetate ascolorless flakes, m.p. 95°-96° C.

Analysis for C₁₁ H₁₆ N₂ O₂ : Calculated %: C, 63.44; H, 7.74; N, 13.45.Found %: C, 63.28; H, 7.71; N, 13.37.

In the same manner as described in Reference 4, the compounds inReferences 5 and 6 were prepared.

Reference 5 4-[2-(1-Pyrrolidinyl)ethoxy]benzaldoxime hydrochloride:

Colorless plates, m.p. 219°-220.5° C. (EtOH).

Analysis for C₁₃ H₁₈ N₂ O₂. HCl: Calculated %: C, 57.67; H, 7.07; N,10.35. Found %: C, 57.57; H, 7.15;: N, 10.25.

Reference 6 4-(2-Piperidinoethoxy)benzaldoxime hydrochloride

Colorless flakes, m.p. 224°-225° C. (EtOH).

Analysis for C₁₄ H₂₀ N₂ O₂. HCl: Calculated %: C, 59.05; H, 7.43; N,9.84. Found %: C, 58.74; H, 7.28; N, 9.64.

Reference 7 4-(2-Piperidinoethoxy)benzylamine

A suspension of 32.3 g of 4-(2-piperidinoethoxy)benzaldoxime in 400 mlof 10% methanolic ammonia was hydrogenated over 3.6 g of Raney nickelcatalyst at a pressure of 50 kg/cm² and at 30° C. The catalyst wasfiltered off and the filtrate was evaporated. The residue was distilledto give 27.7 g of colorless oil, b.p. 185°-190° C. (6 mmHg).

NMR spectrum δ (CDCl₃)ppm: 1.30-1.90 (8H,m), 2.40-2.60 (4H,m), 2.76(2H,t,J=6 Hz), 3.79 (2H,s), 4.09 (2H,t,J=6 Hz), 6.86 (2H,d,J=9 Hz), 7.21(2H,d,J=9 Hz).

In the same manner as described in Reference 7the compounds inReferences 8 and 9 were prepared.

Reference 8 4-[2-(1-Pyrrolidinyl)ethoxy]benzylamine

Colorless oil, b.p. 163°-165° C. (3 mmHg).

NMR spectrum δ (CDCl₃)ppm: 1.53 (2H,br), 1.70-1.90 (4H,m) 2.50-2.75(4H,m), 2.89 (2H,t,J=6 Hz), 3.79 (2H,s), 4.10 (2H,t,J=6 Hz), 6.88(2H,d,J=9 Hz), 7.22 (2H,d,J=9 Hz).

Reference 9 4-[2-(Dimethylamino)ethoxy]benzylamine

Colorless oil, b.p. 142°-144° C. (6 mmHg).

NMR spectrum δ (CDCl₃) ppm: 1.45 (2H,s), 2.32 (6H,s), 2.71 (2H,t,J=6Hz), 3.79 (2H,s), 4.05 (2H,t,J=6 Hz), 6.88 (2H,d,J=9 Hz), 7.21 (2H,d,J=9Hz).

EXAMPLE 1 N-[4-[2-(Dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide

To a cooled solution of 20.0 g of 4-[2-(dimethylamino)ethoxy]benzylaminein 60 ml of toluene was added a solution of 21.7 g of3,4-dimethoxybenzoyl chloride (which was prepared with 19.7 g of3,4-dimethoxybenzoic acid and 38.5 g of thionyl chloride in the usualmanner) in 60 ml of toluene with stirring. The mixture was stirred atroom temperature for 30 minutes. To the mixture was added 120 ml ofwater and 1 ml of concentrated hydrochloric acid. The aqueous layer wasseparated, washed with 20 ml of toluene and made alkaline with 20%sodium hydroxide solution to give a precipitate, which was washed withisopropyl ether, of 37.0 g of pale brownish crystals. Recrystallizationof the crystals from ethanol and isopropyl ether gave the title compoundas colorless needles, m.p. 111°-112° C.

Analysis for C₂₀ H₂₆ N₂ O₄ : Calculated %: C, 67.02; H, 7.31; N, 7.82.Found %: C, 66.96; H, 7.28; N, 7.78.

EXAMPLE 2 N-[4-[2-(Dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamidehydrochloride

A solution of 3.23 g ofN-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide in ethanolwas acidified by the addition of ethanolic hydrogen chloride. Theprecipitate was filtered and washed with a mixture of ethanol andisopropyl ether to give 3.22 g of pale brownish crystals, which wererecrystallized from ethanol as colorless prisms, m.p. 194°-195° C.

Analysis for C₂₀ H₂₆ N₂ O₄. HCl: Calculated %: C, 60.83; H, 6.89; N,7.09. Found %: C, 60.78; H, 6.99; N, 7.05.

EXAMPLE 33,4-Methylenedioxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide:

To a cooled solution of 20.0 g of4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 30 ml of chloroform was added17.7 g of 3,4-methylenedioxybenzoyl chloride (which was prepared with15.9 g of piperonylic acid and 65.3 g of thionyl chloride in the usualmanner). The mixture was stirred at room temperature for 20 minutes andthe solvent was evaporated. 150 ml of water was added to the residue andthe mixture was washed with ethyl acetate. The aqueous layer was madealkaline with potassium carbonate and was extracted with ethyl acetate.The extract was washed with water, dried, and evaporated. The residuewas washed with isopropyl ether to give 30.0 g of colorless crystals,which were recrystallized from ethyl acetate as colorless needles, m.p.93.5°-94.5° C.

Analysis for C₂₁ H₂₄ N₂ O₄ : Calculated %: C, 68.46; H, 6.57; N, 7.60.Found %: C, 68.44; H, 6.65; N, 7.45.

EXAMPLE 4 2,4-Dimethoxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide

To a cooled suspension of 1.82 g of 2,4-dimethoxybenzoic acid in 10 mlof tetrahydrofuran was added 1.09 g of ethyl chloroformate and 1.01 g oftriethylamine. After stirring for 15 minutes, to the mixture was added asolution of 2.00 g of 4-[2-(1-pyrrolidinyl)ethoxy]benzylamine in 5 ml oftetrahydrofuran. The mixture was stirred for 15 minutes and the solventwas evaporated. To the residue was added 10% hydrochloric acid, and thesolution was washed with ethyl acetate. The aqueous layer was madealkaline with potassium carbonate and was extracted with ethyl acetate.The extract was washed with water, dried, and evaporated to give 3.31 gof the title compound as a colorless oil.

Mass spectrum: m/z: 384 (M⁺)

IR spectrum: ν (liquid) cm⁻¹ : 1648 (c=o)

NMR spectrum: δ (CDCl₃) ppm; 1.62-1.97 (4H,m), 2.44-2.76 (4H,m), 2.88(2H,t,J=6 Hz), 3.84 (3H,s), 3.86 (3H,s), 4.09 (2H,t,J=6 Hz), 4.58(2H,d,J=5.5 Hz), 6.46 (1H,d,J=2 Hz), 6.59 (1H,dd,J=9,2 Hz), 6.88(2H,d,J=9 Hz), 7.27 (2H,d,J=9 Hz), 7.99 (1H,br), 8.21 (1H,d,J=9 Hz).

EXAMPLE 54-Amino-5-chloro-N-[4-[2-(dimethylamino)ethoxy]benzyl]-2-methoxybenzamide

To a cooled suspension of 2.49 g of 4-amino-5-chloro-2-methoxybenzoicacid in 15 ml of chloroform were successively added dropwise 1.26 g oftriethylamine and 1.35 g of ethyl chloroformate with stirring. Themixture was stirred at the same temperature for 30 minutes. Next, to themixture was added a solution of 2.00 g of4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of chloroform withstirring. The mixture was stirred at room temperature for 14 hours andthe solvent was evaporated. 10% Hydrochloric acid was added to theresidue and the aqueous solution was washed with ethyl acetate. Theaqueous layer was made alkaline with potassium carbonate and wasextracted with chloroform. The extract was washed with water, dried, andevaporated. The residue was washed with ether to give 3.87 g of slightlybrownish crystals, which were recrystallized from ethanol to givecolorless needles, m.p. 147°-148° C.

Analysis for C₁₉ H₂₄ ClN₃ O₃ : Calculated %: C, 60.39; H, 6.40; N,11.12. Found %: C, 60.28; H, 6.46; N, 11.12.

Further, the free base was converted into the hydrochloride in the usualway using ethanolic hydrogen chloride as in Example 2. Recrystallizationof the hydrochloride from ethanol gave colorless needles, m.p.206.5°-208° C.

Analysis for C₁₉ H₂₄ ClN₃ O₃. HCl: Calculated %: C, 55.08; H, 6.08; N,10.14. Found %: C, 54.86; H, 6.21; N; 9.98.

EXAMPLE 6N-[4-[2-(Dimethylamino)ethoxy]benzyl]-2-methoxy-5-sulfamoylbenzamide

To a cooled suspension of 14.3 g of 2-methoxy-5-sulfamoylbenzoic acid in60 ml of tetrahydrofuran were successively added dropwise 6.25 g oftriethylamine and 7.45 g of pivaloyl chloride with stirring. The mixturewas stirred at the same temperature for 1 hour and then a solution of10.0 g of 4-[2-(dimethylamino)ethoxy]-benzylamine in 40 ml oftetrahydrofuran was added dropwise with stirring. The mixture wasstirred at room temperature for 14 hours and the solvent was evaporated.Hydrochloric acid (10%) was added to the residue and the aqueoussolution was washed with ethyl acetate. The aqueous layer was madealkaline with potassium carbonate to give a precipitate, which waswashed with water and ethyl acetate, of 16.6 g of colorless crystals.Recrystallization of the crystals from ethanol gave the title compoundas colorless needles, m.p. 154°-155° C.

Analysis for C₁₉ H₂₅ N₃ O₅ S: Calculated %: C, 56.00; H, 6.18; N, 10.31.Found %: C, 55.71; H, 6.21; N, 10.02.

Further, the free base was converted into the hydrochloride in the usualway. Recrystallization of the hydrochloride from methanol gave colorlessneedles, m.p. 122.5°-123° C.

Analysis for C₁₉ H₂₅ N₃ O₅ S HCl. 2H₂ O: Calculated %: C, 47.55; H,6.30; N, 8.75. Found %: C, 47.47; H, 5.90; N, 8.72.

EXAMPLE 7 N-[4-[2-(Dimethylamino)ethoxy]benzyl]-5-dimethylaminosulfonyl2-methoxybenzamide

To a cooled suspension of 3.20 g of5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml oftetrahydrofuran were successively added dropwise 1.25 g of triethylamineand 1.34 g of ethyl chloroformate with stirring. The mixture was stirredat the same temperature for 30 minutes and then a solution of 2.00 g of4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran wasadded dropwise with stirring. The mixture was stirred at roomtemperature for 2 hours and the solvent was evaporated. Hydrochloricacid (10%) was added to the residue and the aqueous solution was washedwith ethyl acetate. The aqueous layer was made alkaline with potassiumcarbonate and was extracted with ethyl acetate. The extract was driedand evaporated. The residue was washed with isopropyl ether to give 4.10g of colorless crystals, which were recrystallized from a mixture ofethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C.

Analysis for C₂₁ H₂₉ N₃ O₅ S: Calculated %: C, 57.91; H, 6.71; N, 9.65.Found %: C, 57.69; H, 6.82; N, 9.38.

EXAMPLE 8 N-[4-[2-(Dimethylamino)ethoxy]benzyl]-4-sulfamoylbenzamide

To a cooled solution of 1.50 g of 4-[2-(dimethylamino)ethoxy]benzylamineand 0.87 g of triethylamine in 10 ml of chloroform was added 1.87 g of4-sulfamoylbenzyl chloride, which was prepared from 1.71 g of4-sulfamoylbenzoic acid with 16.3 g of thionyl chloride in the usualway, with stirring. The mixture was stirred at room temperature for 30minutes and the solvent was evaporated. Hydrochloric acid (10%) wasadded to the residue and the aqueous solution was washed with ethylacetate. The aqueous layer was made alkaline with potassium carbonateand was extracted with ethyl acetate. The extract was washed with water,dried, and evaporated. The residue was washed with ethyl acetate to give1.19 g of pale yellow crystals, which were recrystallized from ethanolto give colorless crystals, m.p. 173.5°-174.5° C.

Analysis for C₁₈ H₂₃ N₃ O₄ S: Calculated %: C, 57.28; H, 6.14; N, 11.13.Found %: C, 57.58; H, 6.40; N, 10.95.

EXAMPLE 9 N-[4-[2-(Dimethylamino)ethoxy]benzyl]-4-fluorobenzamide

To a cooled solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamineand 1.14 g of triethylamine in 10 ml of chloroform was added 1.80 g of4-fluorobenzoyl chloride, which was prepared from 1.59 g of4-fluorobenzoic acid with 7.77 g of thionyl chloride. The mixture wasstirred for 30 minutes and the solvent was evaporated. Hydrochloric acid(10%) was added to the residue and the aqueous solution was washed withethyl acetate. The aqueous layer was made alkaline with potassiumcarbonate and was extracted with ethyl acetate. The extract was washedwith water, dried, and evaporated. The residue was washed with n-hexaneto give 3.07 g of pale yellow crystals, which were recrystallized from amixture of ethanol and ether to give colorless needles, m.p. 113°-114.5°C.

Analysis for C₁₈ H₂₁ FN₂ O₂ : Calculated %: C, 68.34; H, 6.69; N, 8.85.Found %: C, 68.31; H, 6.67; N, 8.73.

Further, the free base was converted into the hydrochloride in the usualway. Recrystallization of the hydrochloride from ethanol gave colorlessplates, m.p. 165°-166° C.

Analysis for C₁₈ H₂₁ FN₂ O₂.HCl: Calculated %: C, 61.27; H, 6.28; N,7.94. Found %: C, 61.18; H, 6.29; N, 7.75.

EXAMPLES 10 2-Amino-N-[4-[2-(dimethylamino)ethoxy]benzyl]benzamide

To a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 20ml of ethyl acetate was added 1.04 g of isatoic anhydride. The mixturewas stirred at room temperature for 15 minutes. Hydrochloric acid (10%)was added to the mixture. The aqueous layer was separated, made alkalinewith potassium carbonate and extracted with ethyl acetate. The extractwas washed with water, dried, and evaporated. Recrystallization of theresidue from ethyl acetate gave 1.85 g of colorless pillars, m.p.104°-105° C.

Analysis for C₁₈ H₂₃ N₃ O₂ : Calculated %: C, 68.98; H, 7.40; N, 13.41.Found %: C, 69.07; H, 7.03; N, 13.32.

In the same manner as described in Examples 1 to 10, the compounds ofExamples 11 to 86 were prepared.

The physical and chemical properties of the compounds of Examples 11 to86 are shown in Tables 4 and 5.

    TABLE 4      ##STR9##       Example        melting point   No. R.sub.1 R.sub.2 R.sub.3 R.sub.4     R.sub.5 salt crystals (solvent) Analysis for (Calcd. C;H;N;, Found     C;H;N;)       11 2-OMe 3-OMe H Me Me fumarate colorless 122˜123°     C.sub.28 H.sub.26 N.sub.2 O.sub.4.C.sub.4 H.sub.4 O.sub.4 60.75; 6.37;     5.90 60.62; 6.41; 5.79        needles (EtOH) 12 2-OMe 4-OMe H Me Me --     colorless 75˜76° C.sub.28 H.sub.26 N.sub.2 O.sub.4 67.02;     7.31; 7.82 67.04; 7.26; 7.57        needles (EtOH-iPr.sub.2 O) 13 2-OMe     6-OMe H Me Me -- colorless 130˜131° C.sub.28 H.sub.26     N.sub.2 O.sub.4 67.02; 7.31; 7.82 66.85; 7.29; 7.58        plates     (AcOEt) 14 3-OMe 5-OMe H Me Me -- colorless 71˜72° C.sub.28     H.sub.26 N.sub.2 O.sub.4 67.02; 7.31; 7.82 66.90; 7.12; 7.59     needles (EtOH-iPr.sub.2      O)            15     ##STR10##      H Me Me -- colorlesscrystals 89˜90°(EtOH-iPr.sub.2 O)     C.sub.19 H.sub.22 N.sub.2 O.sub.4 66.65; 6.48; 8.18 66.61; 6.45; 8.03     " " " " hydrochloride colorless 166˜167° C.sub.19 H.sub.22     N.sub.2 O.sub.4.HCl 60.24; 6.12; 7.39 60.13; 6.21; 7.16       needles     (EtOH) 16 3-OMe 4-OH H Me Me -- colorless 129.5˜130.5°     C.sub.19 H.sub.24 N.sub.2 O.sub.4 66.26; 7.02; 8.13 66.34; 7.05; 7.97         plates (AcOEt)           17      ##STR11##      H (CH.sub.2).sub.5 -- yellowneedles 64˜65°(AcOEt-iPr.sub.2     O) C.sub.22 H.sub.26 N.sub.2 O.sub.4 69.09; 6.85; 7.32 69.05; 6.74; 7.19      18 3-OMe 4-OMe H (CH.sub.2).sub.4 -- colorless 93˜95°     C.sub.22 H.sub.28 N.sub.2 O.sub.4 68.73; 7.34; 7.29 68.61; 7.38; 7.09        needles (AcOEt-iPr.sub.2 O) 19 3-OMe 4-OMe H (CH.sub.2).sub.5 --     yellow 113˜114° C.sub.23 H.sub.38 N.sub.2 O.sub.4 69.32;     7.59;7.03 69.49; 7.73; 6.92       needles (AcOEt-iPr.sub.2 O) 20 H H H     Me Me -- colorless 84˜85° C.sub.18 H.sub.22 N.sub.2 O.sub.2 7     2.46; 7.43; 9.39 72.53; 7.25; 9.34        plates (iPr.sub.2 O) 21 4-OH H     H Me Me -- colorless 133˜134° C.sub.18 H.sub.22 N.sub.2     O.sub.3 68.77; 7.05; 8.91 69.04; 7.15; 8.95        scales (EtOH) 22     2-OMe H H Me Me -- colorless 72.5˜73.5° C.sub.19 H.sub.24     N.sub.2 O.sub.3 69.49; 7.37; 8.53 69.40; 7.36; 8.33        needles     (iPr.sub.2      O)  " " " " " hydrochloride colorless 156.5˜157.5°     C.sub.19 H.sub.24 N.sub.2 O.sub.3.HCl 62.54; 6.91; 7.68 62.53; 6.99;     7.38        needles (EtOH) 23 3-OMe H H Me Me -- colorless 66˜68.de     gree. C.sub.19 H.sub.24 N.sub.2 O.sub.3 69.49; 7.37; 8.53 69.49; 7.13;     8.44        needles (iPr.sub.2      O)  " " " " " maleate colorless 100˜101° C.sub.19 H.sub.24     N.sub.2 O.sub.3.C.sub.4 H.sub.4 O.sub.4 62.15; 6.35; 6.30 62.02; 6.26;     6.35        plates (iPrOH-iPr.sub.2 O) 24 4-OMe H H Me Me -- colorless     119˜120° C.sub.19 H.sub.24 N.sub.2 O.sub.3 69.49; 7.37;     8.53 69.47; 7.29; 8.42        needles (EtOH-Et.sub.2 O)  " " " " "     hydrochloride colorless 175˜176° C.sub.19 H.sub.24 N.sub.2     O.sub.3.HCl 62.54; 6.91; 7.68 62.46; 6.97; 7.52        needles (EtOH) 25     4-OEt H H Me Me -- colorless 128˜129° C.sub.28 H.sub.26     N.sub.2 O.sub.3 70.15; 7.65; 8.18 69.93; 7.75; 7.94        needles     (AcOEt)  " " " " " hydrochloride colorless 164˜165°     C.sub.28 H.sub.26 N.sub.2 O.sub.3.HCl 63.40; 7.18; 7.39 63.15; 7.32;     7.23        scales (EtOH-Et.sub.2 O) 26 4-OBu-n H H Me Me -- colorless     131˜132° C.sub.22 H.sub.26 N.sub.2 O.sub.3 71.32; 8.16;     7.56 71.17; 8.26; 7.53        scales (AcOEt) 27 4-OMe H H (CH.sub.2).sub.     4 -- colorless 120˜121° C.sub.22 H.sub.26 N.sub.2 O.sub.3     71.16; 7.39; 7.90 70.93; 7.54; 7.97       needles (AcOEt) 28 4-OEt H H     (CH.sub.2).sub.4 -- colorless 125˜127° C.sub.22 H.sub.28     N.sub.2 O.sub.3 71.71; 7.66; 7.60 71.57; 7.84; 7.52       prisms (AcOEt) 2     9 3-OEt H H Me Me -- colorless 80˜81° C.sub.28 H.sub.26     N.sub.2 O.sub.3 70.15; 7.65; 8.18 70.03; 7.55; 8.09        needles     (iPr.sub.2 O) 30 4-OPr-n H H Me Me -- colorless 117˜119°     C.sub.22 H.sub.28 N.sub.2 O.sub.3 70.76; 7.92; 7.86 70.58; 7.93; 7.81         prisms (AcOEt) 31 3-OMe 4-OEt H Me Me -- colorless 113˜114.degr     ee. C.sub.21 H.sub.23 N.sub.2 O.sub.4 97.72; 7.58; 7.52 67.66; 7.61;     7.50        needles (AcOEt) 32 3-OEt 4-OEt H Me Me -- colorless 127.5.abo     ut. 129° C.sub.22 H.sub.38 N.sub.2 O.sub.4 68.37; 7.82; 7.25     68.39; 7.54; 7.11        needles (AcOEt) 33 3-OEt 5-OEt H Me Me --     colorless 114˜114.5° C.sub.22 H.sub.36 N.sub.2 O.sub.4     68.37; 7.82; 7.25 68.15; 7.73; 7.20        needles (AcOEt) 34 2-OMe     4-NH.sub.2 5-Cl (CH.sub.2).sub.4 -- colorless 144˜146.5°     C.sub.21 H.sub.25 ClN.sub.3 O.sub.3 62.45; 6.49; 10.40 62.49; 6.56;     10.26       needles (EtOH) 35 2-OMe 4-NH.sub.2 5-Cl (CH.sub.2).sub.5 --     colorless 121˜122° C.sub.22 H.sub.28 ClN.sub.3 O.sub.3     63.23; 6.75; 10.05 63.24; 6.80; 9.78       needles (AcOEt) 36 5-SO.sub.2     NHMe 2-OMe H Me Me -- colorless 154˜156° C.sub.26 H.sub.27     N.sub.3 O.sub.5 S.1/2H.sub.2 O 55.80; 6.56; 9.76 56.10; 6.61; 9.77      needles (AcOEt-EtOH) 37 5-SO.sub.2 NH.sub.2 2-OMe H (CH.sub.2).sub.4 -- c     olorless 91˜93° C.sub.21 H.sub.27 N.sub.3 O.sub.5 S.H.sub.2     O 55.86; 6.47; 9.31 55.66; 6.35; 9.06       crystals (EtOH) 38 5-SO.sub.2      NH.sub.2 2-OMe H (CH.sub.2).sub.5 -- colorless 113˜114°     C.sub.22 H.sub.28 N.sub.3 O.sub.5 S.H.sub.2 O 56.76; 6.71; 9.03 56.81;     6.74; 8.84       needles (MeOH)  " " " " hydrochloride colorless     203˜204° C.sub.22 H.sub.29 N.sub.3 O.sub.5 S.HCl 54.09;     6.29; 8.60 53.98; 6.28; 8.39       needles (MeOH) .1/4H.sub.2 O 39     3-SO.sub.2      N.Me.sub.2 4-Cl H Me Me hydrochloride colorless 146˜147°     C.sub.20 H.sub.25 ClN.sub.3 O.sub.4 S.HCl 49.49; 5.81; 8.66 49.55; 5.83;     8.43        needles (EtOH) .1/2H.sub.2 O 40  3-SO.sub.2 N.Me.sub.2 4-Cl     H (CH.sub.2).sub.4 fumarate colorless 110˜111° C.sub.22     H.sub.28 ClN.sub.3 O.sub.4 S 52.83; 5.63; 7.11 52.79; 5.64; 6.95     prisms (EtOH) .C.sub.4 H.sub.4 O.sub.4.1/2H.sub.2 O 41 5-SO.sub.2     NH.sub.2 2-OMe 4-NH.sub.2 Me Me -- colorless 160˜161°     C.sub.19 H.sub.25 N.sub.4 O.sub.5 S 52.89; 6.31; 12.98 52.89; 6.23;     12.98        needles (EtOH) .1/2H.sub.2 O  " " " " " hydrochloride     colorless 134˜136° C.sub.19 H.sub.25 N.sub.4 O.sub.5 S.HCl     47.84; 6.13; 11.75 48.12; 6.27; 11.50        needles (MeOH-AcOEt)     .H.sub.2 O 42 3-SO.sub.2      N Me.sub.2 2-OMe H (CH.sub.2).sub.4 -- colorless 128˜129°     C.sub.23 H.sub.32 N.sub.3 O.sub.5 S 59.85; 6.77; 9.10 59.89; 6.68; 9.10          prisms (EtOH) 43 5-SO.sub.2 NHMe 2-OMe H (CH.sub.2).sub.4 --     colorless 168˜169° C.sub.23 H.sub.29 N.sub.3 O.sub.5 S     59.04; 6.53; 9.39 58.82; 6.24; 9.33       scales (EtOH) 44 2-Cl H H Me     Me -- colorless 66˜67° C.sub.18 H.sub.21 ClN.sub.2 O.sub.2     64.09; 6.42; 8.30 64.24; 6.39; 8.07        needles (iPr.sub.2 O)     .1/4H.sub.2 O  " " " " " hydrochloride colorless 207˜209°     C.sub.18 H.sub.21 ClN.sub.2 O.sub.2.HCl 58.54; 6.00; 7.59 58.30; 6.07;     7.30        scales (EtOH) 45 3-Cl H H Me Me -- colorless 78˜79.degr     ee. C.sub.18 H.sub.21 ClN.sub.2 O.sub.2 64.96; 6.36; 7.59 65.02; 6.37;     8.18        needles (iPr.sub.2 O)  " " " " " hydrochloride colorless     166˜167° C.sub.18 H.sub.21 ClN.sub. 2 O.sub.2.HCl 58.54;     6.00; 7.59 58.27; 6.20; 7.26        scales (EtOH-Et.sub.2 O) 46 4-Cl H H     Me Me -- colorless 105˜106° C.sub.18 H.sub.21 ClN.sub.2     O.sub.2 64.96; 6.36; 8.42 65.05; 6.42; 8.24        scales (EtOH-iPr.sub.2      O)  " " " " " hydrochloride colorless 186˜188° C.sub.18     H.sub.21 ClN.sub.2 O.sub.2.HCl 58.54; 6.00; 7.59 58.46; 6.21; 7.21      scales (EtOH) 47 3-Me H H Me Me hydrochloride colorless 118˜120.de     gree. C.sub.19 H.sub.24 N.sub.2 O.sub.2.HCl 65.41; 7.22; 8.03 65.25;     7.19; 7.83        needles (EtOH-Me.sub.2 CO) 48 4-Me H H Me Me --     colorless 109˜110° C.sub.18 H.sub.24 N.sub.2 O.sub.2 73.05;     7.74; 8.97 73.16; 7.61; 8.78        prisms (iPr.sub.2 O)  " " " " "     hydrochloride colorless 197˜199° C.sub.18 H.sub.24 N.sub.2     O.sub.2.HCl 65.41; 7.22; 8.03 65.20; 7.32; 7.70        plates (EtOH-Et.su     b.2 O) 49 4-Et H H Me Me -- colorless 101˜102° C.sub.18     H.sub.26 N.sub.2 O.sub.2 73.59; 8.03; 8.58 73.65; 7.98; 8.38     pillars (iPr.sub.2 O) 50 2-NO.sub.2 H H Me Me hydrochloride colorless     190˜191° C.sub.18 H.sub.22 N.sub.3 O.sub.4.HCl 56.92; 5.84;     11.06 56.91; 6.05; 10.82        needles (EtOH) 51 3-NO.sub.2 H H Me Me     -- pale yello2 88˜89° C.sub.18 H.sub.22 N.sub.3 O.sub.4     63.96; 6.16; 12.24 62.90; 6.24; 12.18        needles (AcOEt-Et.sub.2 O)     " " " " " hydrochloride colorless 204˜205 C.sub.18 H.sub.22     N.sub.3 O.sub.4.HCl 56.92; 5.84; 11.06 56.95; 6.04; 10.79        needles     (EtOH) 52 4-NO.sub.2 H H Me Me -- pale yellow 153˜154°     C.sub.18 H.sub.22 N.sub.3 O.sub.4 62.96; 6.16; 12.24 62.94; 6.13; 12.18           needles (AcOEt) 53 4-CN H H Me Me -- pale yellow 93˜94.degree     . C.sub.18 H.sub.22 N.sub.3 O.sub.2 70.57; 6.55; 12.99 70.41; 6.42;     12.71        needles (AcOEt-Et.sub.2 O)  " " " " " hydrochloride pale     yellow 182˜183° C.sub.18 H.sub.22 N.sub.3 O.sub.2.HCl     62.63; 6.22; 11.53 62.94; 6.13; 11.25        needles (EtOH) .1/4H.sub.2     O 54 4-tBu H H Me Me -- colorless 135˜137° C.sub.22     H.sub.38 N.sub.2 O.sub.2 74.54; 8.53; 7.90 74.60; 8.28; 7.86     needles (AcOEt) 55 4-N.Me.sub.2 H H Me Me -- colorless 144˜146.degr     ee. C.sub.28 H.sub.27 N.sub.3 O.sub.2 70.35; 7.97; 12.31 70.21; 7.58;     12.02        needles (AcOEt) 56 4-Me H H (CH.sub.2).sub.4 -- colorless     105˜107° C.sub.22 H.sub.28 N.sub.2 O.sub.2 74.53; 7.74;     8.28 74.63; 7.44; 8.19       prisms (AcOEt) 57 4-CN H H (CH.sub.     2).sub.4 -- colorless 102˜103° C.sub.22 H.sub.23 N.sub.3     O.sub.2 72.18; 6.63; 12.03 71.96; 6.49; 11.80       prisms (AcOEt) 58     3-NO.sub.3 H H (CH.sub.2).sub.4 hydrochloride grayish 176˜178.degre     e. C.sub.20 H.sub.23 N.sub.3 O.sub.4.HCl 59.18; 5.96; 10.35 58.90; 5.97;     10.39       brown (EtOH)       needles 59 2-Cl 4-Cl H Me Me -- colorless 1     11˜112° C.sub.18 H.sub.28 Cl.sub.2 N.sub.2 O.sub.2 58.87;     5.49; 7.63 58.89; 5.46; 7.51        needles (C.sub.6 H.sub.6)  " " " " "     hydrochloride colorless 218˜219° C.sub.18 H.sub.28 Cl.sub.2     N.sub.2 O.sub.2.HCl 53.55; 5.24; 6.94 53.41; 5.39; 6.78        scales     (EtOH) 60 3-Cl 4-Cl H Me Me hydrochloride colorless 209.5˜212.degre     e. C.sub.18 H.sub.28 Cl.sub.2 N.sub.2 O.sub.2.HCl 53.55; 5.24; 6.94     53.75; 5.47; 6.89        needles (MeOH) 61 3-Cl 5-Cl H Me Me hydrochlorid     e colorless 159˜160° C.sub.18 H.sub.22 Cl.sub.2 N.sub.2     O.sub.2.HCl 53.55; 5.24; 6.94 53.46; 5.46; 6.71        needles (EtOH) 62     3-Me 4-NO.sub.2 H Me Me -- yellow 88˜90° C.sub.19 H.sub.22     N.sub.3 O.sub.4 63.85; 6.49; 11.76 63.56; 6.61; 11.70        needles     (AcOEt)  " " " " " hydrochloride colorless 170˜171°     C.sub.19 H.sub.22 N.sub.3 O.sub.4.HCl 57.94; 6.14; 10.67 57.66; 6.38;     10.63        prisms (EtOH-Et.sub.2      O) 63 3-Me 4-NO.sub.2 H (CH.sub.2).sub.4 -- pale yellow 113˜114.de     gree. C.sub.22 H.sub.28 N.sub.3 O.sub.4 65.78; 6.57; 10.96 65.49; 6.68;     10.87       prisms (AcOEt) 64 4-Me H H (CH.sub.2).sub.5 -- colorless     90˜91° C.sub.22 H.sub.28 N.sub.2 O.sub.3 74.97; 8.01; 7.95     74.93; 7.81; 7.85       needles (iPr.sub.2 O) 65 2-OEt H H Me Me     hydrochloride colorless 127˜130° C.sub.28 H.sub.28 N.sub.2     O.sub.3.HCl 63.40; 7.18; 7.39 63.14; 7.32; 7.41        prisms (EtOH-n-C.s     ub.6      H.sub.14) 66 2-OH H H Me Me hydrochloride colorless 153˜156.degree     . C.sub.18 H.sub.22 N.sub.2 O.sub.3.HCl 61.62; 6.61; 7.98 61.63; 6.66;     7.95        needles (EtOH) 67 3-OH H H Me Me -- colorless 151˜153.d     egree. C.sub.18 H.sub.22 N.sub.2 O.sub.3 68.77; 7.05; 8.91 68.94; 7.21;     8.98        plates (EtOH) 68 3-SO.sub.2 NH.sub.2 H H Me Me -- colorless     169˜172° C.sub.18 H.sub.22 N.sub.3 O.sub.4 S 57.28; 6.14;     11.13 57.30; 6.07; 11.12        crystals (EtOH) 69 2-Me H H Me Me     hydrochloride colorless 186˜187.5° C.sub.19 H.sub.24     N.sub.2 O.sub.2.HCl 65.41; 7.22; 8.03 65.34; 7.14; 8.00        scales     (EtOH) 70 2-F H H Me Me -- colorless 70˜72° C.sub.18     H.sub.22 FN.sub.2 O.sub.2 68.34; 6.69; 8.85 68.24; 6.57; 8.87     needles (AcOEt-n-C.sub.6 H.sub.14)  " " " " " hydrochloride colorless     139˜142° C.sub.18 H.sub.22 FN.sub.2 O.sub.2.HCl 61.27;     6.28; 7.94 61.25; 6.30; 7.97        needles (EtOH-Et.sub.2 O) 71 3-F H H     Me Me -- colorless 86˜87° C.sub.18 H.sub.22 FN.sub.2     O.sub.2 68.34; 6.69; 8.85 68.34; 6.66; 8.83        needles (iPr.sub.2 O)      " " " " " fumarate colorless 127˜128° C.sub.18 H.sub.22     FN.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4 61.10; 5.83; 6.48 60.94; 5.88;     6.55        plates (EtOH) 72 3-NH.sub.2 H H Me Me hydrochloride colorless      173˜174° C.sub.18 H.sub.22 N.sub.3 O.sub.2.2HCl 55.96;     6.52; 10.88 56.13; 6.49; 10.89        crystals (MeOH-AcOEt) 73 4-NH.sub.2      H H Me Me hydrochloride colorless 171˜173° C.sub.18     H.sub.22 N.sub.3 O.sub.2.2HCl 55.96; 6.52; 10.88 55.89; 6.69; 10;.88        needles (MeOH) 74 3-CN H H Me Me -- colorless 99˜100°     C.sub.18 H.sub.22 N.sub.3 O.sub.2 70.57; 6.55; 12.99 70.65; 6.51; 12.99           crystals (AcOEt-iPr.sub.2 O)  " " " " " hydrochloride colorless     155˜157° C.sub.19 H.sub.22 N.sub.3 O.sub.2.HCl 63.42; 6.16;     11.68 63.32; 6.14; 11.73        prisms (EtOH) 75 3-tBu 4-OH 5-tBu Me Me     -- colorless 142˜144° C.sub.26 H.sub.38 N.sub.2 O.sub.3     73.20; 8.98; 6.57 73.47; 8.96; 6.29        plates (Me.sub.2 CO-iPr.sub.2     O) 76 3-Cl 4-NH.sub.2 5-Cl Me Me hydrochloride pale brown 132˜134.d     egree. C.sub.18 H.sub.22 Cl.sub.2 N.sub.3 O.sub.2.HCl 50.54; 5.42; 9.82     50.55; 5.51; 9.71        needles (EtOH) .1/2H.sub.2 O 77 3-Cl 4-NH.sub.2 5     -Cl (CH.sub.2).sub.4 -- pale brown 63˜64° C.sub.28 H.sub.23     Cl.sub.8 N.sub.3 O.sub.2 58.83; 5.68; 10.29 59.00; 6.04; 10.19     needles (AcOEt) 78 2-F 4-F 5-F Me Me -- colorless 80˜82°     C.sub.18 H.sub.19 F.sub.3 N.sub.2 O.sub.2 61.36; 5.44; 7.95 61.32; 5.71;     7.98        prisms (AcOEt)

    TABLE 5      ##STR12##       Example      Ms spectrum IR spectrum NMR spectrum No. R.sub.1 R.sub.2     R.sub.3 R.sub.4 R.sub.5 m/z (M) ν (liq)cm.sup.-1 δ      (CDCl.sub.3)ppm       79 3-OMe H H (CH.sub.2).sub.4 yellow oil 354 1650 1.66-1.98(4H, m),     2.44-2.76(4H, m), 2.88(2H, t, J = 6HZ),        (C = 0) 3.82(3H, s),     4.09(2H, t, J = 6Hz), 4.61(2H, d, J = 5.5Hz),         6.47(1H, br),     6.97(2H, d, J = 9Hz), 7.20-7.38(6H, m) 80 3-SO.sub.2 NH.sub.2 4-Cl H Me     Me pale yellow oil 413, 411 1648 2.29(6H, s), 2.69(2H, t, J = 5.5Hz),     3.92(2H, br),        (1:3) (C = 0) 3.99(2H, t, J = 5.5Hz), 4.47(2H, d, J     = 5.5Hz), 6.78(2H, d, J= 9Hz),          7.07(1H, t, J = 5.5Hz), 7.49(1H,     d, J = 8.5Hz), 7.92(1H, dd, J = 8.5,          2Hz), 8.32(1H, d, J = 2Hz)     81 3-SO.sub.2 NH.Me 4-Cl H Me Me colorless oil 427, 425 1650 2.32(6H,     s), 2.62(3H, s), 2.71(2H, t, J = 5.5Hz), 4.04(2H, t,        (1:3) (C =     0) J = 5.5Hz), 4.54(2H, d, J = 5.5Hz), 5.88(1H, br), 6.85(2H, d,      J = 9Hz), 7.25(2H, d, J = 9Hz), 7.56(1H, d, J = 8.5Hz), 7.99(1H, dd,           J = 8.5, 2Hz), 8.39(1H, d, J = 2Hz) 82 3-SO.sub.2 NH.sub.2 4-Cl H     (CH.sub.2).sub.4 yellow oil  439, 437 1644 1.55-1.97(4H, m), 2.32-2.72(4H     , m), 2.87(2H, t, J = 6Hz),       (1:3) (C = 0) 4.07(2H, t, J = 6Hz),     4.52(2H, br), 6.82(2H, d, J = 9Hz),         7.09(2H, d, J = 9Hz),     7.36(1H, d, J = 8.5Hz), 7.70(1H, br),         7.83(1H, dd, J = 8.5,     2Hz), 8.34(1H, d, J = 2Hz) 83 3-SO.sub.2 NH.Me 4-Cl H (CH.sub.2).sub.4     yellow oil 453, 451 1644 1.57-1.98(4H, m), 2.34-2.77(4H, m), 2.88(2H, t,     J = 5.5Hz),       (1:3) (C = 0) 4.08(2H, t, J = 5.5Hz), 4.53(2H, d, J =     5.5Hz), 6.84(2H, d, J = 9Hz),         7.16(1H, br), 7.25(2H, d, J =     9Hz), 7.55(1H, d, J = 8.5Hz),         8.03(1H, dd, J = 8.5, 2Hz),     8.40(1H, d, J = 2Hz) 84 3-SO.sub.2 N.Me.sub.2 4-OMe H Me  Me colorless     oil 435 1644 2.32(6H, s), 2.71(2H, t, J = 5.5Hz), 2.82(6H, s), 3.95(3H,     s),         (C = 0) 4.04(2H, t, J = 5.5Hz), 4.53(2H, d, J = 5.5Hz),     6.86(2H, d, J = 9Hz),          7.03(1H, d, J = 8.5Hz), 7.27(2H, d, J =     9Hz), 8.10(1H, dd, J = 8.5,          2.5Hz), 8.25(1H, d, J = 2.5Hz) 85     3-SO.sub.2 N.Me.sub.2 4-OMe H (CH.sub.2).sub.4 pale yellow oil 461 1646     1.62-1.89(4H, m), 2.45-2.75(4H, m), 2.83(6H, s), 2.89(2H, t,        (C =     0) J = 6Hz), 3.96(3H, s), 4.10(2H, t, J = 6Hz), 4.55(2H, d, J = 5.5Hz),            6.88(2H, d, J = 9Hz), 7.05(1H, d, J = 8.5Hz), 7.27(2H, d, J =     9Hz),         8.12(1H, dd, J = 8.5, 2Hz), 8.22(1H, d, J = 2Hz) 86 2-F     4-F 5-F (CH.sub.2).sub.4 yellow oil 378 1660 1.57-2.10(4H, m), 2.48-2.80(     4H, m), 2.90(2H, t, J = 6Hz),        (C = 0) 4.10(2H, t, J = 6Hz),     4.48-4.72(2H, m), 6.67-7.14(2H, m),         6.89(2H, d, J = 9Hz),     7.25(2H, d, J =      9Hz), 7.73-8.13(1H, m)

What is claimed is:
 1. Amide-compound selected from N-[4-[2-(dimethylamino)ethoxyl-benzyl]-3,4-dimethoxybenzamidepharmacologically-acceptable acid-addition salts thereof.
 2. A compoundof claim 1 which isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-3,4-dimethoxybenzamide.
 3. Acompound of claim 1 which isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-3,4-dimethoxybenzamidehydrochloride.
 4. A pharmaceutical composition useful to activategastric motor function comprising one or more compounds as claimed inclaim 1, in an amount effective for such purpose, together with acompatible, pharmaceutically-acceptable carrier or coating.
 5. Apharmaceutical composition useful to activate gastric motor functioncomprising the compound of claim 2, in an amount effective for suchpurpose, together with a compatible, pharmaceutically-acceptable carrieror coating.
 6. A pharmaceutical composition useful to activate gastricmotor function comprising the compound of claim 3, in an amounteffective for such purpose, together with a compatible,pharmaceutically-acceptable carrier or coating.
 7. A method for thetreatment of a subject suffering from an ailment associated withinadequate gastric motor function, comprising the step of administeringto the said subject an amount of an amide compound selected from thoserepresented by the formula (I) ##STR13## wherein R₁ represents hydrogen,lower alkoxy, hydroxy, lower alkyl, halogen, amino which can besubstituted by lower alkyl, nitro, cyano, sulfamoyl which can besubstituted by lower alkyl, R₂ represents hydrogen, lower alkoxy,hydroxy, lower alkyl, halogen, amino, nitro, and wherein R₁ and R₂ canbe combined to form methylenedioxy R₃ means hydrogen, lower alkyl,halogen, or amino, and wherein R₄ and R₅ may be the same or differentand each represents lower alkyl and wherein R₄ and R₅ may be combinedtogether with nitrogen to form 1-pyrrolidinyl or piperidino, andpharmacologically-acceptable acid-addition salts thereof, which iseffective for the alleviation of such ailment.
 8. Method of claim 7,wherein the compound isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-3,4-dimethoxybenzamide.
 9. Methodof claim 7, wherein the compound isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-3,4-dimethoxybenzamidehydrochloride.
 10. Method of claim 7, wherein the compound is3,4-Methylenedioxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide. 11.Method of claim 7, wherein the compound is3,4-Dimethoxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide. 12.Method of claim 7, wherein the compound isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-4-ethoxy-3-methoxybenzamide. 13.Method of claim 7, wherein the compound isN-[4-[2-(dimethylamino)ethoxy]-benzyl]-2-methoxy-5-sulfamoylbenzamide.14. Method of claim 7, wherein the compound is4-Amino-5-chloro-2-methoxy-N-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzamide